Rheumatoid factors (RFs) are autoantibodies against autologous IgG, and are found in abundant quantity in the sera of most patients with rheumatoid arthritis, a progressive crippling disease with unknown etiology. Although RFs may contribute to chronic tissue damage in the rheumatoid synovium, they have been found in the sera of some normal individuals. Furthermore, IgM anti-IgG autoantibodies/RFs are produced during secondary immune responses in humans and animals. This suggests that RF-like antibodies are a physiological component of the immune system. Thus, in order to have a better understanding of the basic role or human RFs, we plan: (i) to identify the major cross-reactive idiotypes (CRIs) of human IgM-RFs; (ii) to define the genetic basis of these CRI-positive RFs; and (iii) to elucidate the physiology of RF-genes in the host immune network. Specifically, we will use synthetic peptides (corresponding to the complementary-determining regions, CDRs, of RFs) to induce anti-CRIs which recognize "primary structure-dependent" CRIs on the separated heavy and light chains of RFs. In essence, these antibodies identify genetic markers on autoantibody variable regions. Using such antibodies, we have found that 80% of human monoclonal IgM-RF share homologous light chains, suggesting that these RF light chains derive from a single VL gene or a family of closely related VL genes in the germ line. This observation has led us to construct the amino acid sequence of the putative RF light chain gene, and to obtain a human k chain cDNA (NG9) for isolating the VLRF gene from an established human fetal liver genomic library. Encouraged by these preliminary results, we intend to use the same approach to study the major RF heavy chain CRIs and their genes. At the same time, the peptide-induced anti-CRIs will be used to elucidate the physiological expression of major human RF genes, by characterizing the quantity and quality of RF-CRI positive immunoglobulins. In addition, separated heavy and light chains, which bear RF-CRI markers, will be used to identify the reacting autologous antibodies. We believe these studies will help us to re-evaluate the biological role of RFs in normals as well as patients, and to design an effective idiotype manipulation toward controlling the production of undesirable autoantibodies in human.